Hot Topics: Cushing’s Disease and Acromegaly

Mark E Molitch, M.D.Division of Endocrinology, Metabolism & Molecular Medicine

Northwester University Feinberg School of MedicineChicago, IL 60611

Disclosures• Research Support:

Corcept - mifepristone Novartis - Pasireotide, OctreotideIpsen/Tercica – LanreotideChiasma – Oral OctreotideEndo - Octreotide implants

• ConsultantCorceptNovartisAbbott Laboratories

CRH

ACTH

Cortisol

Adrenals

PituitaryDopamine agonists

Somatostatin analogs

KetoconazoleMitotane

MetyraponeEtomidate

Mifepristone

GR

Cushing’s Disease Treatment

Tissues

Adrenal Steroid Inhibition - Ketoconazole

X

X

XX

X

Side chain cleavage

3β-HSD

17α-OH

17α-OH3β-DH

21-OH 21-OH

11β-OH 11β-OH

17,20 lyase

17,20 lyase3β-DH

aldo synthaseX

X

X

X

X

Treatment of Cushing’s Disease with Ketoconazole

0200400600800

1000120014001600

Urinary Free Cortisol

(nmol/24h)

Sonino et al Tabarin et alPre Post Pre Post

Percent Normalized 94% 100%

Sonino et al, Clin Endocrinol1991;35:347Tabarin et al, Clin Endocrinol1991;34:63

Ketoconazole for Cushing’s Syndrome

Side effects:

• Hepatic toxicity

• Gastrointestinal symptoms

• Rash

• Strong CYP3A4 inhibitor (substrates include amiodarone, carbamazepine, amitriptyline, SSRIs, benzodiazepines, calcium channel blockers, statins, colchicine)

• Hypogonadism in men

• Teratogenic

Dosing

200 to 1600 mg daily divided BID or TID

Proton pump inhibitor use may impair absorption

Monitoring

Liver function tests

Serum and urine cortisol

Long-term may “escape” from control

Dopamine Receptor Expression and Function in Corticotroph Tumors

• Dopamine D2 receptors found in 80% of corticotroph tumors

• Of those with D2 receptors, 100% had significant inhibition of ACTH secretion in vitro with cabergoline

• Of those with D2 receptors, in vivo 60% had significant reduction of cortisol levels and 40% had normalization of cortisol levels with 1-3 mg cabergoline per week

• So, 80% x 40% = 32% of all patients (since measurement of D2 receptors not routine) can expect control of hypercortisolism with cabergoline

Pivonello et al., JCEM 2004;89:2452

Effect of Cabergoline at doses of 1-3 mg/week on Urinary Free Cortisol Levels in Patients

0

300

600

900

1200

0 1 2 3

Months

Uri

na

ry c

ort

iso

l/2

4h

Pivonello et al., JCEM 2004;89:2452

Mifepristone• Mifepristone was initially developed as a

progesterone receptor antagonist and used widely as an abortifacient (RU486)

• Mifepristone is also a glucocorticoid receptor antagonist with greater affinity for the receptor than either cortisol or dexamethasone

• Since 1985, 51 Cushing’s Syndrome patients treated with Mifepristone had been reported prior to the large, multicenter SEISMIC trial

Mifepristone Mechanism of Action

Mifepristone competes with an agonist for binding to the GR

GRE

Antagonist-bound GR prevents agonist-bound GR from binding to glucocorticoid response elements (GREs)Antagonist-bound GR/GRE complex does not cause transcription or any downstream effects

mifepristone

agonist

GR

Complextranslocates

to the nucleus

nucleus

Complex bindsto GRE

nucleus

MifepristoneSEISMIC Study Design

• 24 week open label study of MIFE 300 –1200 mg/day

• 50 subjects with Cushing’s syndrome who failed multi-modality therapy

Starting dose 300 mg po qd Escalation until Week 10

Screen 42 days

D1 Wk6 Wk10 Wk16

24 Week Treatment Safety 6 week

Wk24

stopMifepristone

Screened: 84Enrolled: 50

Completed: 34Early Termination (ET): 16

Mifepristone Main Eligibility Criteria• ACTH-dependent and independent

Cushing’s syndrome• Intolerant of or not responsive to other therapy• DM2/IGT and/or hypertension• At least 2 signs and symptoms of Cushing’s

syndrome• No concomitant treatment for Cushing’s

syndromeStable doses of mitotane allowed in adrenal cancer

Mifepristone Baseline Characteristics (n=50)

• Cushing’s disease - 4342 failed previous surgery18 also had pituitary radiation

Average time from radiation 32 ± 7 months• Ectopic ACTH - 4• Adrenal cancer - 3• Mean age - 45 ± 12 yr• Females - 35 (70%)• 25 with diabetes (C-DM)• 21 with hypertension without diabetes (C-HT)

Improvement in Glucose Tolerance on oGTT(C-DM) with Mifepristone

14

p=.01

*

n=25

n=20

Improvement in HbA1c in C-DM with Mifepristone

p<0.001vs baseline

N=25 N=22N=20

p<0.001 vs baseline

Decrease in Insulin Levels with Mifepristone(C-DM not on insulin and C-HT)

# p= .01 vs baseline* p =.03 vs baseline

## **

Subjects not taking insulin (N=24)

mean ± SD

Decrease in Weight with Mifepristone

↓ 5.7 ± 1.5%p<0.001

vs Baseline

mean ± SE

-12

-10

-8

-6

-4

-2

0

Decrease in Waist Circumference with MifepristoneM

ean

chan

ge fr

om b

asel

ine

(cm

)

C-DM(N=19)

C-HT(N=13)

Overall(N=32)

Females

-12

-10

-8

-6

-4

-2

0

C-DM(N=6)

C-HT(N=8)

Overall(N=14)

Males* P<0.001 vs baseline

122.4 111.3 117.9 132.5 111.4 120.4Baseline (cm):

**

Decreases in Diastolic BP or BP Medications with Mifepristone in all

Subjects with Hypertension at Baseline

n (%)(n=40)

Subjects with either ≥5 mmHg reduction from baseline in DBP OR had a reduction in antihypertensive medications at Week 24/ET

Responder 21 (52.5)Nonresponder 19 (47.5)

Quality of Life (SF-36) Improved with Mifepristone

N= 46 baseline, 40 W24/ET

p = .01p = .02

mean ± SD

ACTH and Cortisol Dynamics (Cushing’s disease)

21

Adverse EffectsHypokalemia

• Likely due to mineralocorticoid receptor activation in setting of rising cortisol with glucocorticoid receptor blockade

• Common but generally mild to moderate and associated with alkalosis and edema

3 cases of severe hypokalemia (defined as K≤ 2.5) during treatmentResponded well to potassium replacement and spironolactone

Adverse EffectsAdrenal Insufficiency

• Glucocorticoid withdrawal symptoms frequently seen

• Two subjects had adrenal insufficiency noted as AE

One treated with dexamethasoneOne event resolved without glucocorticoid

• Five additional subjects had AEs potentially consistent with adrenal insufficiency and were treated with glucocorticoid

Mifepristone was held and restarted at lower dose without AI recurrence

Adverse EffectsEndometrial Hyperplasia

• Mifepristone has known anti-progestin activity

• Increases in endometrial thickness in half of the women

• 5 cases of vaginal bleeding2 with prolonged bleeding after stopping mifepristone

• 3 women underwent D&C for non-resolved endometrial thickening after stopping mifepristone

sst-1 sst-2 sst-3 sst-4 sst-50.00

0.05

0.10

0.15

sst/hprt

Pasireotidetargets 4 of 5 sst

de Bruin C et al. Rev Endocr Metab Disord 2009Bruns C et al. Eur J Endocrinol 2002

Somatostatin Receptor Subtype mRNA in Corticotroph Adenomas (n=30)

LJ Hofland et al. Eur J Endocrinol 2005Batista DL et al. JCEM 2006

Pasireotide Study Design329 patients screened

Core study

900 μg bid(unblinded)*

1200 μg bid(unblinded)*

Month 12

Open label

Extension

Day 1

Screening

Month –1

Screening

Washoutof other meds

Partially blind

Month 6

Primary efficacy(Normalization of UFC without dose up-titration before 6 months)

600 μg bid

900 μg bid

*For patients who had a mean baseline UFC ≥ 2xULN with a 3-month UFC > 2xULN ORFor patients who had a mean baseline UFC 1.5–2xULN with a 3-month UFC above their baseline UFC

Randomization(n = 162)

Pasireotide 900 μg sc bid

Pasireotide 600 μg sc bid

Month 3

Double blind

n = 80

n = 82

↓↑ dose titrationper investigator

Optional extension phase

Patients with UFC ≤ 2xULN and less than baseline at month 3 continued at their randomized dose, double blind, until month 6

All other patients were unblinded and the dose wasincreased by 300 μg bid until month 6, and were considered

nonresponders for the primary efficacy analysis

Baseline demographics by randomized dose

Overall

(n = 162)

600 µg bid

(n = 82)

900 µg bid

(n = 80)

Mean age, years 40.2 40.5 39.9

Female, n (%) 126 (77.8) 62 (75.6) 64 (80.0)

Mean time since diagnosis, months 54.0 53.4 54.5

Cushing’s disease status

Persistent/recurrent, n (%) 135 (83.3) 67 (81.7) 68 (85.0)

De novo, n (%) 27 (16.7) 15 (18.3) 12 (15.0)

Previous surgery, n (%) 128 (79.0) 64 (78.0) 64 (80.0)

Previous medication, n (%) 78 (48.1) 36 (43.9) 42 (52.5)

Previous pituitary irradiation, n (%) 7 (4.3) 3 (3.7) 4 (5.0)

2500

Change in UFC from baseline to month 6in the 103 patients with baseline and month-6 UFC measurements

Individual patients sorted by baseline UFC

UFC

(μg/

24h)

0

180

360

540

720

1400

600 µg bid900 µg bid

ULN†

Baseline UFCMonth 6 UFCMonth 6 UFC ≤ ULN*

†Reference line is the upper limit normal UFC, which is 52.5 μg/24h (145 nmol/24h)

Median percent UFC change from baseline was -47.9% in both groups

Mean UFC over time

Month

Mea

n U

FC ±

SE (μ

g/24

h)

0 3 6 9 12

543

471

400

326

254

181

109

36

900 µg bid600 µg bid

ULN: 52.5 µg/24h (145 nmol/24h)

n = 153 144 132 131 123 116 111 93 77

Similar trends seen for:• Serum & salivary cortisol• Plasma ACTH

Within 1–2 months, patients with inadequate biochemical responsecan be identified with 90% accuracy

900µg bid group met the preset statistical criterion for efficacy:the lower bound of the 95% CI for a dose group had to be >15%

600µg bid

N=82

900µg bid

N=80OverallN=162

6-month response, n (%) 12 (14.6) 21 (26.3) 33 (20.4)

95% Confidence Interval (7.0, 22.3) (16.6, 35.9) (14.2, 26.6)

12-month response, n (%) 11 (13.4) 20 (25.0) 31 (19.1)

Primary Efficacy Results6-month response: normal UFC without uptitration at 3 months

Median percent UFC change from baseline was -47.9% for both groups

UFC Response According to Baseline UFC Level

600 µg bid (n = 82)900 µg bid (n = 80)

Baseline UFC shown as fold elevations above ULN

Patients achieving normal UFC at month 6 (%)

Higher rate of UFC normalization with lower baseline UFC

0 10 20 30 40 50 60

>1.5 to ≤2x

>2x to ≤5x

>5x 1/224/39

10/407/26

7/141/12 (31%)

(26%)

(8%)

450

360

270

180

90

0

450

360

270

180

90

0

135

133

131

129

127

125

123

121B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

Mea

n U

FC ±

SE (μ

g/24

h) Mean B

P ±SE (m

mH

g)

Month

Systolic blood pressure (SBP)

888786858483828180

B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

Mean SBPMean UFC

Diastolic blood pressure (DBP)

Significant Decrease in Blood Pressure and UFC

Significant change from baseline to month 12 was observed for:

SBP -6.1 mmHg

DBP -3.7 mmHg

Mean DBPMean UFC

84

82

80

78

76

74

72

450

360

270

180

90

0B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

Month

Mean UFC (μg/24h) Mean weight (kg)Mean UFCMean weight

Decrease in Weight and UFCSignificant decrease in weight of 6.7 kg

from baseline to month 12

Month

Improvement in HRQoL* and UFC

B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

Mean UFC (μg/24h) HRQoL score450

360

270

180

90

0

54

52

50

48

46

44

42

40

Mean UFCHRQoL score

Significant (11.1 points) improvement from baseline to month 12

*Measured via CushingQoL (Webb et al. Eur J Endocrinol 2008;158:623)

Pasireotide: Side Effects• Safety of pasireotide was generally similar to

other somatostatin analogues, except for hyperglycemia– Most frequently reported AEs were gastrointestinal

• As expected with an effective treatment for Cushing’s disease, some patients (8%) experienced hypocortisolism– Responded to dose reduction and/or temporary

corticosteroid substitution• 72.8% of patients had at least one hyperglycemia-

related AE, – HbA1c increased in both dose groups

Changes in Glycemia

Mean fastingplasma glucose(mg/dL)

600 µg bid (n=82)900 µg bid (n=80)

90

100

110

120

130

140150

Baseline Day 15 Month 3 Month 6 Month 12

Changes in Glycemia

Mean HbA1c

(%)600 µg bid (n=82)900 µg bid (n=80)

5

6

7

8

Baseline Month 2 Month 6 Month 12

Changes in Glycemia• Of 67 patients normoglycemic at baseline, 14

(21%) remained normal, 29 (43%) became pre-diabetic and 23 (34%) became diabetic during treatment

• 2 other studies conducted in healthy volunteers – Pasireotide reduced incretin & insulin secretion,

without affecting insulin sensitivity– Treatment with incretin-based

antihyperglycemic agents liraglutide and vildagliptin significantly reduced pasireotide-induced hyperglycemia

Combination Drug Therapy

Feelders, et al NEJM (2010) 362:1846

Cushing’s disease n = 17, sequential medication addition

Pasireotide(max 750mcg)

Cabergoline(max 0.75mg)

Ketoconazole(max 600 mg)

Combination Drug Therapy

11 Patients with severe, refractory Cushing’s Diseasetreated with high-dose therapy combining mitotane (3.0–5.0 g/24 h), metyrapone (3.0–4.5 g/24 h), and ketoconazole (400–1200 mg/24 h) concomitantly. Kamenický P et al. JCEM 2011;96:2796

Cushing’s Summary & Conclusions• Ketoconazole remains the mainstay of medical

treatment of Cushing’s syndrome• Cabergoline may be tried in patients with

Cushing’s disease• Other current therapies, such as metyrapone,

mitotane much less successful• Mifepristone offers high success clinically and

metabolically but may be difficult to use because of difficulty in titrating dose and adverse effects of adrenal insufficiency and menorrhagia

• Pasireotide may be helpful in small percentage of patients with Cushing’s disease but has a major adverse effect of hyperglycemia

• Combination therapy may have a role in difficult to manage cases

41

Medical Therapy for Acromegaly

Dopamine Agonists• bromocriptine• cabergolineSomatostatin Analogs• octreotide• lanreotideGH Receptor Antagonist• pegvisomant

Medical Therapy for Acromegaly

Somatostatin Analogs• octreotide• lanreotideGH Receptor Antagonist• pegvisomant

Effects of Adjunctive Therapy With Cabergoline Following Surgery and/or Irradiation on IGF-I Levels in Patients With

Acromegaly

Series N % with Normal IGF-I

Colao (1997) 11 0Abs (1998) 64 39

Cozzi (1998) 18 27Moyes (2008) 15 33

TOTAL 108 32

Colao et al., JCEM. 1997;82:518.Abs et al., JCEM. 1998;83:374.Cozzi et al., Eur J Endocrinol. 1998;139:516.Moyes et al., Eur J Endocrinol 2008;159:541.

alaala

thrthr

trptrp

glygly cyscys lyslys asnasn phephe phephe

lyslys

phephethrthrcyscys serser

Human somatostatin

Amino acids essential

for receptor binding

Somatostatin Analogs

• inhibits multitude of hormones

• T ½ 3 minutes

•binds all 5 receptor sub-typesvalval

DtrpD

trp

Dbnal

Dbnal cyscys tyrtyr

lyslys

cyscysThrolThrol

Lanreotide

thrthr

DtrpD

trp

Dphe

Dphe cyscys phephe

lyslys

cyscysThrolThrol

Octreotide

Comparison of Octreotide LAR to Lanreotide AutogelSummary of 5 Studies

(n=75)

(n=75)

Murray RD, Melmed S. JCEM 2008;93:2957

Equivalent Efficacy of Octreotide LAR and Lanreotide Depot

32 patients switched from

octreotide 20 or 30 mg

monthly to 90 or 120 mg

lanreotide Depot

Salvatori et al., Pituitary 2010;13:115

Comparison of Approved Somatostatin Analogs

Octreotide LAR Lanreotide DepotRequires

reconstitutionReady to use,

prefilled syringe

10, 20, 30 mg 60, 90, 120 mg

IM q 4 wks (~1.5 inch needle)

Deep SC q 4 wks (~3/4 inch needle)

Volume; 2-2.5 mL Volume; 0.3-0.5 mL

Healthcare professional

administration

Self or partner administration

possible

Product Information Somatuline® Depot, 2007. Bevan JS, et al. Clin Endocrinol (Oxf). 2008;68(3):343-349. Product Information Sandostatin LAR® Depot, 2006.

Long-acting

octreotide

Lanreotide depot

Tumor Changes After Octreotide Therapy Expressed as a Percentage of the Pre-

treatment Volume in 20 Macroadenomas

0%

20%

40%

60%

80%

100%

120%

Baseline 12 Weeks 24 Weeks 48 Weeks

Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.

Perc

enta

ge o

f Orig

inal

Siz

e

Author Journal Year

Kristof Acta Neuro 1999

Biermasz JCEM 1999

Plockinger Acta Neuro 2005

Losa J Neurosurg 2006

Abe EJE 2001

Author Journal Year

Barkan JCEM 1988

Stevenaert Acta Endo 1993

Colao JCEM 1997

*Carlsen JCEM 2008

*Mao Eur J Endo 2010

*Randomized, controlled trials

Negative Studies Positive Studies

Does Pre-op Somatostatin Analog Treatment Improve Surgical Outcomes?

Primary Therapy: Octreotide (SQ)

•Mea

n IG

F-I (

x103

U/L

)No Previous Treatment n=25

Previous Treatment n=80

6

4

2

00 0.5 1.0 1.5 2.0

Treatment Duration (years)

2.5 3.0 3.5

5

3

1

Newman CB, et al. J Clin Endocrinol Metab. 1998;83:3034-40.

Summary of Surgical Debulking on the Responsiveness to Somatostatin Analogs

StudyNormal GH

Pre-op

Normal GH Post-

op

Normal IGF1

Pre-op

Normal IGF1 Post-op

Colao1 12/86 49/86 9/86 48/86

Jallad2 4/11 5/11 0/11 9/11

Petrossi3 7/24 13/24 8/19 18/23

Totals (control)

23/121 (19%)

67/121 (55%)

17/121 (14%)

75/121 (62%)

1Colao et al. JCEM. 2006;91:85-92.2Jallad, et al. Clin Endo. 2007;67:310-315.3Petrossians, et al. Eur J Endo. 2005;152:61-66.

Benefits of Adding Cabergoline to Somatostatin Analogs

Cozzi et al Clin Endocrinol 2004;61:209

Patients are ranked by PRL (µg/l)

level shown on the x-axis

IGF-I percentchange

during SA +CAB compared

to SA alone

60

40

20

0

-20

-40

-60

-80

-100

4 5 6 7 8 8 8 8 8 9 12 16 17 20 21 23 24 50 60

IGF-

1 %

cha

nge

Extension of Time Between 20 mg Octreotide LAR Doses in Patients With

Acromegaly

Turner et al Clin Endocrinol 2004;61:224

Weeks Between Injections

Final Dose Frequency8

7

6

5

4

3

2

1

04 6 8 10 12 off

No.

of P

atie

nts

Serum IGF-I(ng/mL)

500

1000

1500

2000

2500

Age (years)55+16-24 25-39 40-54

PegvisomantIGF-I at Baseline and after 12 months

(N=90)

van der Lely et al Lancet 2001:358;1754

97% normalisation of IGF-I

-2

-1

0

1

2

3

4

6 12 18 24 30 36

Time (months)

change in

volume (cm3)

no radiationradiation

Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant for > 6 Months

van der Lely et al Lancet 2001:358;1754

Tumor Enlargement While Receiving Pegvisomant

• 9 patients had tumor enlargement while taking Pegvisomant– 1 patient, no RT, had increase in tumor

volume from 1.61 cc to 1.93 cc. – 6 patients had progressive growth before

initiating pegvisomant. – 2 patients with stable tumors while on

octreotide experienced enlargement after octreotide discontinuation but remained stable on long-term pegvisomant therapy.

Jimenez et al., Eur J Endocrinol. 2008;159:517

Neggers SJ, et al. JCEM 2007;92:4598

25

45

65

85

105

125

IGF-

I (nm

ol/L

)

30 40 50 60 70Age (yrs)

Monthly somatostatin analogWeekly added pegvisomant 40 mg*

Weekly Pegvisomant Added to Somatostatin Analogs in Resistant Patients Normalizes IGF-I

*9 pts required > 100 mg/wk & 4 pts required 160 mg/wk

n=31 Therapy (35–149 wk)

German Pegvisomant Observational Study

• 20/371 with elevated (>3x Nl) transaminases– 7 had gall stones

• Drug withdrawn in 7 with normalization in 6– Restarted in 3 with no reappearance of

elevated transaminases• Drug continued in 11 with spontaneous

normalization of elevated transaminases in 10

Buchfelder et al., Eur J Endocrinol 2009;161:S3

Pegvisomant‐induced Liver Injury Related to UGT1A1*28 Polymorphism of Gilbert’s Syndrome

• Gilbert’s syndrome – unconjugated hyperbilirubinemia due to decreased hepatic glucuronidation activity

• Uridine diphosphate‐5’glucuronosyltransferase 1A1 (UGT1A1) conjugates bilirubin.– The UGT1A1*28 polymorphism has 2 extra bases in 

promoter region, resulting in a 70% reduction in transcriptional activity & therefore reduced glucuronidation activity. 

• In study of 36 acromegalic patients treated with pegvisomant in Spain– 10 pts (28%) developed LFT abnormalities– 43% of Carriers of UGT1A1*28 had abnormal LFT’s– 7% of wild type UGT1A1 had abnormal LFT’s– Also more frequent in males than females

Bernabeu et al., JCEM 2010;95:2147

Investigational Drugs

VapreotideDopastatinOctreotide ImplantPasireotideOctreolin

Investigational Drugs

GH

Weeks0 5 10 15 20 25

02468101214161820

IGF‐1

Weeks0 5 10 15 20 25

100

200

300

400

500

From Chieffo C et al, ENDO 2011

Octreotide Implant (84 mg) Suppression of GH and IGF-1

Endo Pharmaceuticals

Petersenn S et al, JCEM 95:2781, 2010

Pasireotide (SOM230) – Effects on GH and IGF-1

Transient Permeability Enhancer (TPE)Induces increased intestinal paracellular permeation

Octreolin

Chiasma

Chiasma

Octreolin Inhibits GH Secretion in Rats

Octreolin – Pharmacokinetic Results in Normal Subjects

Chiasma

Summary: Acromegaly• Somatostatin analogs - remain the

mainstay of medical therapy– Depot somatostatin implants– Pasireotide– Oral somatostatin

• Cabergoline– Worth a try in mild cases– Often helpful added to somatostatin analogs

• Pegvisomant– Can switch from somatostatin analogs– Can add to somatostatin analogs (epecially if

large tumor residual)– Watch out for transaminase abnormalities

(especially if have Gilbert’s syndrome)

Thank You